Chemotherapy is the most frequently applied anticancer therapy because of its powerful anticancer effect. Nevertheless the use of chemotherapy often is restricted because of serious side effects and toxicity. Efforts to develop selective chemotherapy that targets tumors as opposed to healthy tissue have focused on targeted delivery of chemotherapeutic agents to tumor cells, such as by using antibodies or peptides that recognize and bind to molecules expressed preferentially in tumor cells but not normal cells. However, wide use of such drugs is limited since such drugs can only be administered to patients whose tumor cells express the target molecules. Moreover, recent research has shown that even within a given patient tumor cells may exhibit intratumoral heterogeneity, with genetic phenotypes differing among cancer cells within a single tumor tissue. This means that even if a biopsy confirms the expression of the target molecule for a given drug, all tumor cells may not express the target, thereby limiting the therapeutic effectiveness of the drug. Furthermore, even when the majority of the tumor tissue expresses the target molecule, the drug still may affect other cells with which it comes into proximity or contact, causing side effects or toxicity.
In further efforts to address these problems, prodrugs have been developed that may be specifically activated in tumor cells and tumor tissue. For example, U.S. Pat. No. 7,445,764 describes a conjugate of a cleavable matrix metalloproteinase (MMP) cleavable peptide and the anticancer drug doxorubicin. US Pat. App. Pub. 2010/0111866 discloses a possible variation of that prodrug conjugated to maleimide. US Pat. App. Pub. 2010/0111866 discloses a prodrug conjugate in the form of maleimide-hydrazone-doxorubicin. US Pat. App. Pub. 2013/0338422 describes a prodrug conjugate of a peptide sequence—DEVD (SEQ ID NO: 4)—and doxorubicin. However, these conjugates suffer from one or more of poor efficacy and poor selectivity, and/or require frequent dosing.
Thus, there remains a need for chemotherapy that works selectively in tumor cells and does not harm normal tissue, such as prodrugs that exhibit good efficacy with minimal side effects.